The tumor necrosis factor superfamily (TNFSF) consists of at least 19 ligands and 30 receptors (TNFRSF) that are differentially and temporally expressed by both lymphoid and non-lymphoid lymphoid cells. In CD3+ T cells, TNFSF signals function in both antigen specific and non-specific ways to support various phases of an immune response including polarization, expansion, effector function, contraction, memory and death. TNFSF15 (TL1A) is the ligand for TNFRSF25 (DR3, hereafter referred to as TNFR25) and can modulate TNFR25-expressing T and NKT cells either positively or negatively by triggering TRADD or FADD signaling cascades via the death domain-containing cytoplasmic tail of TNFR25. TNFR25 signaling is an important contributor to the pathology observed in a range of auto-inflammatory conditions including asthma, inflammatory bowel disease (IBD), experimental autoimmune encephalomyelitis (EAE) and rheumatoid arthritis (RA). Antibody blockade of TL can prevent acute asthma in mice and genetic knockout of TNFR25 significantly blunts the pathologic events in experimental models of EAE or RA. TL contributes to the development of these disease by enhancing polarization, differentiation and effector function of NKT, Th2 and Th17 cells.